UC Irvine

Early-life adversity (ELA) is a risk factor for human affective disorders involving dysregulated reward behaviors. In our limited bedding and nesting mouse model, ELA induces anhedonia-like behaviors in adult male mice while increasing motivation for rewards in adult females, indicating sex-dependent disruption of reward circuit operations. Searching for potential underlying circuit mechanisms of these disruptions of reward behavior, we identified a novel projection from the basolateral amygdala (BLA) to the nucleus accumbens (NAc) that expresses the stress-sensitive neuropeptide corticotropin-releasing hormone (CRH), together with the neurotransmitter GABA. To test the contribution of this projection to reward deficits in adult male and female mice reared in ELA conditions, we conducted the following experiments: Adult male and female CRH-Cre mice raised in control or ELA conditions received bilateral excitatory or inhibitory Cre-dependent DREADDs in the BLA, with clozapine N-oxide or vehicle delivered bilaterally to the NAc medial shell during reward behaviors. Cell identity was determined via immunostaining and electrophysiology. Tissue clearing, light sheet fluorescence microscopy, and deep learning pipelines were used to map brain-wide CRH BLA axonal projections. Bilateral chemogenetic manipulations in male mice demonstrated inhibitory effects of the CRH/GABA BLA→NAc projection on reward behaviors in control mice and inhibiting the projection rescued reward deficits in ELA male mice. In females, neither excitation nor inhibition influenced reward seeking behaviors. Molecular and electrophysiological cell-identities of the projection did not vary by sex. By contrast, comprehensive whole-brain mapping uncovered subtle differences in axonal terminals in the NAc as well as elsewhere, which were both sex- and ELA-dependent. Because these changes did not explain the apparent lack of effect of bilateral chemogenetic manipulations of the projection on female reward behaviors, we tested the hypothesis that ipsilateral and contralateral CRH/GABA BLA→NAc projections may have opposing effects on reward behavior that cancel out when both are manipulated concurrently. Results of ongoing studies support this hypothesis. In summary, the CRH/GABA BLA→NAc projection that influences reward behaviors in males differs structurally and functionally in females, uncovering potential mechanisms for the profound sex-specific impacts of ELA on reward behaviors. Further investigation of this projection will give us a deeper understanding of intrinsic sex differences in the organization of the reward circuitry and the effects of ELA on reward behaviors that underlie many mood disorders.